Crohn's disease and ulcerative colitis (Inflammatory bowel disease or IBD) are chronic relapsing disorders of the intestinal tract that may also have systemic manifestations. Symptoms can be debilitating and include abdominal pain and bloody diarrhea. These disorders are generally accepted to result from aberrant immune recognition of the normal commensal microbiota, often associated with an underlying genetic predisposition. They typically manifest with acute and chronic inflammation (granulomatous in the case of Crohn's disease), tissue injury, scarring and predisposition to adenocarcinoma. Additionally, the intestine is the site of other inflammatory conditions including celiac disease, enteric infection and others. Current IBD therapy involves inflammatory suppression with local 5-aminosalicylates, systemic corticosteroids and/or immunosuppressants, or use of endogenous biologicals (anti-TNF monoclonal antibodies (Infliximab) and others). These approaches present complications of systemic immunosuppression and other toxicities. Thus, there is a need to identify improved therapeutic approaches for these diseases.
Traditionally, delivery of most IBD therapeutics has been accomplished by local enema, oral ingestion or systemic infusion. For biologics in particular, injection and oral administration are not ideal because they cannot survive serum proteases, the harsh environment of the gastrointestinal tract, or clearance processes in blood and tissue. Encapsulation of drugs into polymeric carriers can mitigate these limitations.
Nanoparticles have been investigated for a variety of gut applications including vaccination, diabetes, and IBD. Wilson et al., report orally delivered thioketal nanoparticles loaded with TNF-alpha-siRNA target inflammation and inhibit gene expression in the intestines. See Nature Materials, 2010, 9(11): 923-928. Specific biological molecules have been immobilized on nanoparticle surfaces to direct uptake. Russell-Jones reports the use of targeting agents to increase uptake and localization of drugs to the intestinal epithelium. See Journal of Drug Targeting, 2004, 12(2):113-123.
Cohen et al. report enhanced cell penetration of acid-degradable particles functionalized with cell-penetrating peptides. See Bioconjugate Chemistry, 2008, 19(4):876-881. Takayama et al. report enhanced intracellular delivery using arginine-rich peptides by the addition of penetration accelerating sequences (Pas). Journal of Controlled Release, 2009, 138(2):128-133.
Bhavane et al. report the triggered release of ciprofloxacin from nanostructured agglomerated vesicles. See Int J Nanomedicine. 2007, 2(3): 407-418.
Lambert et al., report thiol-exchange in DTSSP crosslinked peptides is proportional to cysteine content. See Protein Sci, 2011, 20(10):1682-91.
References cited herein are not an admission of prior art.